Recent studies have indicated that the interleukin-12/interferon-g (IFN-g) axis is important in mycobacterial infection susceptibility. Using an intronic (CA) n polymorphic microsatellite marker within the IFN-g receptor-1 (IFNGR1) gene, we have compared the allelic frequencies of this marker in hospitalized tuberculosis patients (n ¼ 120) with that of controls (n ¼ 87) from Rijeka, Croatia. We identified 13 (CA) n alleles in the tuberculosis patients, whereas only 10 were found in the controls. A significant difference between one allelic marker and the control group was observed (P ¼ 0.02, 95% confidence interval 0.14-0.94), suggesting a possible protective association. In contrast, several other allelic markers showed a trend towards association with the disease. We also found a trend towards an increased frequency in homozygosity of one allelic marker in patients (11.7%) as compared with controls (4.6%). We conclude that there is no evidence for disease association of the IFNGR1 gene marker in Mendeliantype (single-allele) inheritance. However, our results also suggest that unidentified allelic variations in the IFNGR1 gene might elevate or decrease the risk in this ethnic population, as a part of the multigenic predisposition to tuberculosis.
Genetic susceptibility to tuberculosis includes several unknown yet different loci each contributing to a small extent. Intronic polymorphisms within the interferon-g (IFN-g) gene IFNG Tþ874A and IFNG Gþ2109A correlate with the IFN-g production in vitro, and the frequency of potential high IFN-g producers was previously reported by others to be lower in patients than in controls from Sicily. The aim of this study was to determine whether there is an association between polymorphisms in the IFN-g gene and predisposition to tuberculosis. We analysed two IFNG SNPs (Tþ874A and Gþ2109A) in patients (n ¼ 253) hospitalized in Rijeka (Croatia) and controls (n ¼ 519) from the same area. Onefifth of the controls were healthy contacts of the diseased, and the rest were blood donors. IFNG alleles, their predicted haplotypes or genotypes were not associated with disease susceptibility. Thus, we could not reproduce results from Sicilian case-control study. However, T/Tþ874 (possible high IFN-g producer) and þ874A/A (putative low producer) genotypes were associated with microscopically positive-negative forms of disease. Haplotypes (Tþ874A and Gþ2109A) based on a prediction by software PHASE and subsequent genotype analysis corroborated these findings. Patients had significantly higher frequency of genotypes without T at þ874 (AA/AA; AA/AG and AG/AG) in microscopyor bacterial culture-positive groups compared with their negative counterparts. These data suggest an association with disease severity rather than susceptibility to tuberculosis in Croatian Caucasian population.
Proinflammatory conditions leading to activation of macrophages via interferonc bear an important role in host defence against intracellular bacteria such as Mycobacterium tuberculosis (Mt). Interleukin-17 plays a similar role, as it appears to be also an activator of macrophages. Recently, the TLR-10 was identified as an anti-inflammatory factor that exerts its action via association with the TLR-2 chain at the cell surface of macrophages, the latter being an Mt-binding protein.We have previously found that gene polymorphisms that either inactivate the TLR2 gene product or have a dominant-negative role are associated with tuberculosis (TB) in Croatian population. We have now extended our survey and found that single nucleotide polymorphism (SNP) in TLR10 (rs11096957) is associated with risk for TB. Homozygotes carrying the A allele are associated with predisposition to disease as analysed by the dominant model of inheritance. In contrast, SNPs in the proinflammatory IL17A and IL17F genes (rs2275913 and rs763780, respectively), found previously to correlate with the disease occurrence in Chinese population, were not significantly associated with tuberculosis in the Croatian population.
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